Dickkopf proteins influence lung epithelial cell proliferation in idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with unknown pathogenesis. The WNT/b-catenin pathway has recently been reported to be operative in epithelial cells in IPF. Dickkopf (DKK) proteins are known to regulate WNT signalling via interaction with Kremen (KRM) receptors, yet their expression and role in the adult lung and in IPF has not been addressed.We analysed the expression, localisation and function of DKK and KRM proteins in IPF lungs using Western blotting, quantitative RT-PCR, immunohistochemistry, ELISA and functional in vitro studies.Enhanced expression of DKK1 and DKK4 and KRM1 was detected in lung homogenates of IPF patients compared with transplant donors. Immunohistochemistry revealed that DKK1 was predominantly localised in basal bronchial epithelial cells. Furthermore, prominent expression of all proteins was observed in hyperplastic alveolar epithelial cells in IPF. Quantitative measurement of DKK1 revealed enhanced protein expression in the bronchoalveolar lumen of IPF patients. Finally, functional studies using human bronchial and alveolar epithelial cell lines demonstrated that WNT-induced epithelial cell proliferation is regulated by DKK1 in a dosedependent fashion.In summary, DKK proteins are expressed in the lung epithelium in IPF. DKK proteins influence epithelial cell proliferation and may, therefore, be suitable therapeutic targets for IPF.

Prokineticin 1 induces Dickkopf 1 expression and regulates cell proliferation and decidualization in the human endometrium

“…Wnt signalling has been proposed to stimulate cellular proliferation during the menstrual cycle (Hou et al ., 2004; Jeong et al ., 2009; Wang et al ., 2009), and DKK1 is known to inhibit the proliferation of epithelial cells in several tissue types, including the intestine (Pinto et al ., 2003; Kuhnert et al ., 2004), lung (Pfaff et al ., 2011) and thymus (Osada et al ., 2010). We hypothesized that one of the functional roles of PROK1-induced DKK1 expression may be as a negative regulator of endometrial epithelial cell proliferation.…”

Respiratory microbiome and epithelial interactions shape immunity in the lungs

“…125 Dikkopf (DKK) proteins regulate Wnt signalling via interaction with Kreme (KRM) receptors, 126 and the Wnt/b-catenin pathway has been implicated in IPF. 127,128 DKK1 expression is increased in lung and bronchoalveolar lavage (BAL) fluid of IPF patients. In addition to being located in hyperplastic alveolar cells, the strongest expression is observed in basal bronchial epithelial cells.…”

Distinct Roles of Wnt/β-Catenin Signaling in the Pathogenesis of Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis

“…Blockades of the Wnt/ β -catenin pathway showed an attenuated experimental fibrosis in mice [44, 81]. The perturbation of Wnt-pathway was directly correlated with abnormal myofibroblast activation [61], EMT [49, 82, 83] and fibrotic process amplification [84], although an increased expression of Wnt inhibitor DKK1 was found to predominantly localize in basal bronchial and hyperplastic alveolar epithelial cells of human IPF lung relative to transplanted donor lungs [60]. For example, an increased Wnt3A protein in fibrotic alveolar epithelia, accompanied by enhanced concentrations of interleukin 1 β (IL-1 β ) and IL-6, was found in bronchoalveolar lavage fluid (BALF) from patients with IPF [67].…”